Enhancement in selective mitochondrial association by direct modification of a mitochondrial targeting signal peptide on a liposomal based nanocarrier

Yamada, Yuma; Harashima, Hideyoshi

doi:10.1016/j.mito.2012.09.001

Cited by 39 publications

(29 citation statements)

References 37 publications

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“…The envelopes were composed of 1, 2-dioleoyl-sn- The modification of the MTS peptide resulted in a gradual increase in the diameter of the MITOPorter, and aggregation occurred when with MTS exceeded 2.5 mol% (Table S1). This tendency 4 corresponded to a previous report showing that it is difficult to maintain envelope-structures in the presence of high densities of the MTS peptide (12). To overcome this problem, we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-Mal-PEG (Mal-PEG-DSPE) (Nippon Oil and Fats Co.; Tokyo, Japan) as an anchor between the MTS-peptide and the envelopes of the MITO-Porter.…”

Section: Main Textsupporting

confidence: 90%

“…We previously showed that MTS enhanced the mitochondrial targeting of nanoparticles in cell homogenates (12), however this was not the case, when living cells were used. We conclude that this contradiction was largely the result of the cell environment, where there are many cytoskeletons and a high density of cell components inside the cells.…”

Section: To Evaluate the Mitochondrial Targeting Activity Of The Mts-mentioning

confidence: 94%

“…The nanocarriers were then used to determine if MTS would be a useful ligand for the selective mitochondrial delivery of a nanoparticle (12). In that study, using cell homogenates, we observed that MTS-modified liposomes efficiently accumulated in mitochondria.…”

Section: Main Textmentioning

confidence: 98%

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Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide

Kawamura

Yamada

Yasuzaki

et al. 2013

Journal of Bioscience and Bioengineering

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This study focused on the intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide (MTS). The nanocarriers showed an efficient cellular uptake, and the MTS had a positive effect on their mitochondrial targeting. This is the first report of an intracellular observation of nanocarriers modified with MTS. Main textInnovative medicine development would be accelerated by the nanocarriers that target a specific organelle, such as the nucleus, mitochondria, the golgi apparatus, the endoplasmic reticulum, all of which are promising targets for therapeutic drugs. Mitochondria are intimately involved in maintaining the homeostasis of vital physiological functions (1) and a dysfunction is a causative factor in a variety of human diseases (2-4). Thus, mitochondria represent a promising therapeutic target, and the delivery of a wide variety of molecules have been reported to date (5-7). The use of an organelle targeting signal tag would make it possible to selectively deliver exogenous proteins and RNA to mitochondria (8-11). However, the issue of whether these signal tags would be useful ligands for the targeting of a nanoparticle with a diameter of more than 100 nm to a specific target has not been demonstrated to date.In a previous study, we reported on the development of nanocarriers equipped with a mitochondrial targeting signal peptide (MTS), which permits the selective delivery of certain types of proteins to mitochondria. The nanocarriers were then used to determine if MTS would be a useful ligand for the selective mitochondrial delivery of a nanoparticle (12). In that study, using cell homogenates, we observed that MTS-modified liposomes efficiently accumulated in mitochondria.While the results indicated that MTS has the potential for functioning as a ligand for nanoparticles, the utility of such signal tags have not yet been demonstrated in living cells.The purpose of this study was to validate whether the presence of MTS on a surface of a nanoparticle enhances their targeting to mitochondria, as well as endogenous mitochondrial proteins 3 in living cells. We report herein on the intracellular observation of an MTS-modified nanocarrier using the Dual Function (DF)-MITO-Porter system, which permits the efficient cytosolic delivery of MTS-modified nanocarriers to be achieved (13-15). We first attempted to develop a DF-MTS-MITOPorter modified with MTS, and optimized the preparation. The cellular uptake efficiency of the carriers was evaluated by means of flow cytometry analyses. Intracellular observations using confocal laser scanning microscopy (CLSM) permitted us to compare the DF-MTS-MITO-Porter and DF-R8-MITO-Porter, a conventional DF-MITO-Porter, in terms of mitochondrial targeting.To observe the intracellular trafficking of MTS-modified nanocarriers, we attempted to construct a DF-MTS-MITO-Porter, by a high density of octaarginine (R8)-modification to enhance cellular uptake (16), incorporating an endosome-fusogenic lipid envelope for endosomal escape (17, 18) an...

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Section: Main Textsupporting

confidence: 90%

Section: To Evaluate the Mitochondrial Targeting Activity Of The Mts-mentioning

confidence: 94%

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Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide

Kawamura

Yamada

Yasuzaki

et al. 2013

Journal of Bioscience and Bioengineering

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“…Previous reports showed that the conjugation or direct modification of MTS permitted a macromolecule such as a protein, DNA and a liposomal nanocarrier to be delivered to mitochondria [8][9][10][11][12] . On the other hand, some researchers have reported the use of a mitochondrial RNA aptamer for mitochondrial delivery.…”

Section: Introductionmentioning

confidence: 99%

A Dual-Ligand Liposomal System Composed of a Cell-Penetrating Peptide and a Mitochondrial RNA Aptamer Synergistically Facilitates Cellular Uptake and Mitochondrial Targeting

Yamada

Furukawa

Harashima

2016

Journal of Pharmaceutical Sciences

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“…Biolistic methods enable DNA transfer to mitochondria using heavy particles coated with DNA; however, successful delivery has been limited to simple organisms, such as the yeast Saccharomyces cerevisiae [60]. Other strategies for delivery use nanocarriers, such as MITO-Porter, a liposome-based vector used for delivery to the mitochondrial matrix, in a process involving membrane fusion [62]; inclusion of a mitochondrial targeting signal (MTS) peptide with MITO-Porter enhanced mitochondrial delivery [63]. Liposome-like carriers derived from dequalinium (DQAsomes) have been used to deliver a minimitochondrial genome with a GFP gene into the mitochondrial compartment of macrophage cells using GFP fluorescence to monitor delivery [64].…”

Section: Cellular Models Of Mitochondrial Diseasementioning

confidence: 99%

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

et al. 2013

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Enhancement in selective mitochondrial association by direct modification of a mitochondrial targeting signal peptide on a liposomal based nanocarrier

Cited by 39 publications

References 37 publications

Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide

Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide

A Dual-Ligand Liposomal System Composed of a Cell-Penetrating Peptide and a Mitochondrial RNA Aptamer Synergistically Facilitates Cellular Uptake and Mitochondrial Targeting

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

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